Work with the enzymes glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and pyruvate kinase has shown the activity of these enzymes in the liver to be nutritionally regulated. On the basis of the level of activity of glucose-6-phosphate dehydrogenase and the level of the enzyme protein determined by antibody precipitation, a model of nutritional regulation of glucose-6-phosphate dehydrogenase has been proposed. This model states that while the rate of synthesis of this enzyme protein is unaffected by changes in dietary pattern from fasting to high-fat or to high-carbohydrate diets, the level of liver enzyme activity changes greatly. It is highest on carbohydrate and lowest on fat. It is proposed that fat metabolites (e.g. free fatty acids and acyl-coenzyme A compounds) irreversibly inactivate the enzyme, and that new enzyme synthesis, which is required to yield the active enzyme on the high carbohydrate diets, takes place with no change in rate of synthesis, but with production of highly active enzyme. Therefore, under conditions of primarily carbohydrate metabolism, the proportion of the enzyme which is active is high, while two other laboratories still state that the nutritional regulation of this enzyme is via induction of enzyme protein synthesis, the induction being brought about by carbohydrate feeding. This grant application is thus first concerned with obtaining absolute proof as to which of these two nutritional regulatory mechanisms (on both of which data has now been published) is true.